Recent radioimmunotherapy (RIT) clinical trials with 90Y-chimeric T84.66 anti-CEA demonstrate the feasibility of dose-intensification through stem cell support and the feasibility of combining RIT with 5-FU chemotherapy. Results indicate that clinically meaningful outcomes are achievable with cT84.66. Results also demonstrate that the primary limitations of 90Y-cT84.66 are its immunogenicity and hematopoi-etic toxicity which limit the number and frequency of therapy cycles. Further refinements in the antibody construct and in how RIT is combined with other systemic therapies are therefore needed. To more effectively integrate RIT with multi-agent chemotherapy, the next generation of Phase I clinical trials will focus on the most promising areas and will evaluate strategies that: 1) combine RIT with more potent radiosensitizing chemotherapy agents. This should result in chemotherapy doses that are potentially radioenhancing without significantly adding to hematopoietic toxicity; 2) utilize more prolonged continuous infusion chemotherapy schedules that have significantly less hematopoietic toxicity; and 3) incorporate regional delivery of radioenhancing chemotherapy and RIT to further improve on the therapeutic ratio. Trials will also evaluate two improved therapy constructs derived from cT84.66: a humanized version of T84.66 and the minibody, an intermediate molecular weight (80 kD), faster clearing construct. A humanized construct should prove less immunogenic and allow for a greater number of therapy cycles in combination with chemotherapy. The minibody demonstrates even higher tumor/marrow dose ratios compared to cT84.66. Due to faster clearance, it is predicted to have less hematopoietic toxicity and immunogenicity making it better suited for combined modality therapy. Finally, RIT directed toward other breast tumor targets will be evaluated. Specifically, the anti-HER2/neu antibody, Herceptin, will be evaluated in biodistribution and Phase I therapy trials radiolabeled with 111In and 90Y. Herceptin has properties that make it attractive for RIT due to its anti-tumor effects, radiation/chemotherapy enhancing effects, and minimal immunogenicity. Project 5 involves the concerted efforts of multiple clinical and basic science Divisions and therefore fully incorporates the multi-disciplinary team approach that is a unique strength of this Program Project.